Comparison of TCDD-elicited genome-wide hepatic gene expression in Sprague–Dawley rats and C57BL/6 mice

Abstract

Although the structure and function of the AhR are conserved, emerging evidence suggests that downstream effects are species-specific. In this study, rat hepatic gene expression data from the DrugMatrix database (National Toxicology Program) were compared to mouse hepatic whole-genome gene expression data following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For the DrugMatrix study, male Sprague–Dawley rats were gavaged daily with 20 μg/kg TCDD for 1, 3 and 5 days, while female C57BL/6 ovariectomized mice were examined 1, 3 and 7 days after a single oral gavage of 30 μg/kg TCDD. A total of 649 rat and 1386 mouse genes (|fold change|≥1.5, P1(t)≥0.99) were differentially expressed following treatment. HomoloGene identified 11,708 orthologs represented across the rat Affymetrix 230 2.0 GeneChip (12,310 total orthologs), and the mouse 4×44K v.1 Agilent oligonucleotide array (17,578 total orthologs). Comparative analysis found 563 and 922 orthologs differentially expressed in response to TCDD in the rat and mouse, respectively, with 70 responses associated with immune function and lipid metabolism in common to both. Moreover, QRTPCR analysis of Ceacam1, showed divergent expression (induced in rat; repressed in mouse) functionally consistent with TCDD-elicited hepatic steatosis in the mouse but not the rat. Functional analysis identified orthologs involved in nucleotide binding and acetyltransferase activity in rat, while mouse-specific responses were associated with steroid, phospholipid, fatty acid, and carbohydrate metabolism. These results provide further evidence that TCDD elicits species-specific regulation of distinct gene networks, and outlines considerations for future comparisons of publicly available microarray datasets.

Modern methodologies and tools for human hazard assessment of chemicals

“…The acute hepatotoxicity of TCDD in mice following a single dose was found to correlate with changes in gene expression, which in turn were correlated with hepatic TCDD levels (Kopec et al, 2013). Similar conclusions were made in a further study (Nault et al, 2013b) when the genome-wide hepatic gene expressions elicited by TCDD were compared in vivo between Sprague-Dawley rats and C57BL/6 mice. However, in that study, only 16 orthologues were differentially expressed across all three species, demonstrating species-specific gene expression profiles of TCDD despite the conservation of the AhR and its signalling mechanism.…”

Low‐dose food contaminants trigger sex‐specific, hepatic metabolic changes in the progeny of obese mice

“…Accordingly, our data constitute a proof-of-concept model addressing the hypothesis of possible cumulative metabolic adverse effects of a pollutant mixture as suggested with reprotoxicity stud- ies (41,42). This is especially important considering the doses used in the present study, which are Ն3 orders of magnitude lower than doses commonly used in toxicological studies with the exception of BPA (2,19,(43)(44)(45) and relatively close to the doses that human beings may be exposed to (16,21,23,46). This study focused on the liver because it is the major site of detoxification, and it is known that drug dispo-sition is altered in fatty liver (29).…”

Sex-related differences in murine hepatic transcriptional and proteomic responses to TCDD

“…A point mutation leads to splicing-generated alteration of the transactivation domain of the H/W rat AHR rendering it refractory to TCDD toxicities while the wild-type L-E rat is one of the most sensitive responders (Pohjanvirta et al, 1998). These differing sensitivities have allowed researchers to compare and contrast the transcriptomic responses to TCDD across species (Boverhof et al, 2006;Boutros et al, 2008;Dere et al, 2011;Forgacs et al, 2013;Nault et al, 2013) and between strains/lines within a species (Franc et al, 2008;Pohjanvirta, 2009;Yao et al, 2012).…”